We propose to develop a contrast agent for photoacoustic imaging targeted to the receptors of vascular endothelial growth factor (VEGFR), so it can be accumulated and retained in tumor endothelial cells by VEGFR-mediated endocytosis. VEGFR are over expressed in angiogenic tumor vasculature from the very early stages of tumor development and therefore VEGFR imaging can be used for early diagnosis as well as for image-guided optimization and management of anti-angiogenic therapy. In order to enhance conversion of light into acoustic signal and increase the sensitivity of detection of abnormal levels of VEGFR in vivo by photoacoustic imaging, we will multiplex near-infrared fluorescent dye indocyanine green on a dendrimer scaffold, and then conjugate the derivatized dendrimer to VEGF. We will test this tracer for photoacoustic imaging of VEGFR in the established model of tumor vascular remodeling in response to anti-angiogenic therapy. For this project we combine the expertise and achievements of three groups, the experts in developing of targeted tracers for imaging of VEGFR in angiogenic vasculature, innovative imaging hardware and software for photoacoustic imaging of tumor lesions, and novel derivatives of ICG for imaging. This study will provide the first-in-class targeted PAI tracer and establish the feasibility of targeted photoacoustic imaging of VEGF receptors in tumor vasculature. If successful, might provide a safe and cost-effective alternative to nuclear imaging for cancerous lesions located at the depths less than 2-3 cm. In Phase II we will establish feasibility of this tracer for early diagnostic of relatively deep tumor lesions, discrimination of malignant and benign lesions, and perform late pre-clinical development of the tracer. PUBLIC HEALTH RELEVANCE: Receptors of vascular endothelial growth factor (VEGFR) are over expressed in angiogenic tumor vasculature from the very early stages of tumor development, therefore VEGFR imaging can be used for early diagnosis and image-guided optimization of anti-angiogenic therapy. We propose to develop a contrast agent for photoacoustic imaging that will be targeted to these receptors, so it can be accumulated and retained in tumor endothelial cells by specific receptor-mediated endocytosis. In order to enhance conversion of light into acoustic signal and increase the sensitivity of detection, we will multiplex a near-infrared fluorescent dye indocyanine green on a dendrimer scaffold, and then site-specifically conjugate the derivatized dendrimer to targeting protein, VEGF. We will test this tracer for photoacoustic imaging of VEGFR in the established model of tumor vascular remodeling in response to anti-angiogenic therapy. Thus study will provide the first-in-class targeted tracer for photoacoustic imaging of VEGFR, and might enable a safe, cost-effective alternative to nuclear imaging for detection of cancerous lesions located at the depths less than 2-3 cm.